Abstract

The unique metabolic demands of the brain point to the critical nature of cerebral small vessel integrity for overall brain and cognitive health. Given the lack of any disease-modifying treatments, new avenues for Alzheimer’s disease (AD) prevention and treatment are urgently needed. This dissertation takes a population neuroscience approach to examine potential promoters of cerebral small vessel integrity for cognitive disorder prevention. Existing methods of evaluating cerebral small vessel integrity focus on neuroimaging markers distal to small vessel disease and fail to evaluate the vessels themselves. To address this limitation, I developed a method using 7T susceptibility-weighted imaging (SWI) magnetic resonance imaging (MRI) for direct small vein measurement in older adults; I examined associations with potential small vessel integrity promoters cross-sectionally and found that the APOE*4 allele was associated with small vein tortuosity. In my second paper, a randomized controlled trial, I found that increasing physical activity and brain-derived neurotrophic factor late in life may improve cerebral small vein health profiles as measured by 7T SWI. In an era when multimorbidity is common among older adults, interactions involving vascular and cardiometabolic risk factors (VCMRF) are critical to evaluate in order to effectively target preventions and treatments—the promise of precision medicine. I evaluated associations of interactions of interest with incident dementia and cognitive impairment in a large population-based cohort with 10 years of follow-up. I found that the risk of all-cause dementia conferred by stroke was even greater among those with congestive heart failure; the beneficial effects of alcohol consumption on overall cognitive performance varied by stroke history; and in exploratory results, the detrimental effect of age on AD dementia risk was lower among those who walked more. Taken together, my findings point to physical activity and VCMRF reduction as potential strategies to promote cerebral small vessel integrity for cognitive disorder prevention and suggest that growth factors such as brain-derived neurotrophic factor should be evaluated further. These strategies for prevention could reduce late-life cognitive disorder prevalence as well as attendant disability and costs, goals of great public health significance.